ABSTRACT The overarching goal of this project is to further improve the differential diagnosis of bvFTD and its underlying neuropathologies in the individual patient, addressing practical limitations to diagnosis both in the clinic and in clinical research settings. Despite substantial advances over the last decades in the clinical and bench science of bvFTD, there are still impediments to progress in this area. First, though in a research setting we have become expert at differentiating bvFTD from various amnestic and non-amnestic variants of AD, bvFTD and AD are still routinely mistaken for each other in both primary and tertiary care centers, demonstrating that community providers still need practical, clinically realistic approaches to differentiating bvFTD and AD. To this end, we will develop a brief, targeted clinical evaluation that is sensitive and specific for the clinical diagnosis of bvFTD versus AD. Second, identification of the molecule responsible for the bvFTD syndrome in an individual patient -- tau, TDP43, or FUS ? remains challenging, even in a research environment where advanced diagnostic tools are available. Thus we will study novel biomarkers such as tau imaging, CSF biomarkers, DNA polymorphisms and RNA expression patterns for their value for in-vivo separation of the bvFTD molecular subtypes. Finally, in both community settings and expert FTD centers, bvFTD and primary mood disorders (MD) such as major depressive disorder (MDD) and bipolar affective disorder (BD) are frequently mistaken for each other. Direct comparison is needed to guide their differentiation, thus we will systematically examine groups of MDD and BD patients with a comprehensive set of neurologic measures and compare them to our bvFTD patients. This will also be an opportunity to explore the clinical presentations of the subset of MD patients in whom biomarkers of neurodegeneration are found. To accomplish our goals, we propose the following aims and activities: AIM 1: Identify a set of measures that can discriminate bvFTD from AD at a high level of accuracy and combine them into a brief clinical assessment protocol that could realistically be adopted in clinic. The clinical, imaging, and laboratory data collected in the previous 14 years of this PPG will be analyzed and a standardized clinical battery will be developed that is sensitive to the diagnosis of bvFTD and to the separation of bvFTD from AD and from healthy older controls. Over the next four years this battery will be validated prospectively, using a tiered approach to model cut-points where shifts in sensitivity/specificity occur with the addition of specific clinical tests that incur additional financial and time costs. AIM 2: We will examine the benefit of more recently developed biomarker approaches to diagnosis in our bvFTD patients to determine which measures best segregate the molecular subtypes of bvFTD. AIM 3: Comprehensively evaluate patients with MD (MDD and BD), matched by age (40-70 years) to our bvFTD patients, to identify features differentiating bvFTD from MD. AIM 4: Determine the frequency of neurodegenerative biomarkers in MD patients and evaluate clinical differences in biomarker positive MD patients.